Tuesday, July 28, 2009

The Diet-Heart Hypothesis: Subdividing Lipoproteins

Two posts ago, we made the rounds of the commonly measured blood lipids (total cholesterol, LDL, HDL, triglycerides) and how they associate with cardiac risk.

Lipoproteins Can be Subdivided into Several Subcategories

In the continual search for better measures of cardiac risk, researchers in the 1980s decided to break down lipoprotein particles into sub-categories. One of these researchers is Dr. Ronald M. Krauss. Krauss published extensively on the association between lipoprotein size and cardiac risk, eventually concluding (source):

The plasma lipoprotein profile accompanying a preponderance of small, dense LDL particles (specifically LDL-III) is associated with up to a threefold increase in the susceptibility of developing [coronary artery disease]. This has been demonstrated in case-control studies of myocardial infarction and angiographically documented coronary disease.

Krauss found that small, dense LDL (sdLDL) doesn't travel alone: it typically comes along with low HDL and high triglycerides*. He called this combination of factors "lipoprotein pattern B"; its opposite is "lipoprotein pattern A": large, buoyant LDL, high HDL and low triglycerides. Incidentally, low HDL and high triglycerides are hallmarks of the metabolic syndrome, the quintessential modern metabolic disorder.

Krauss and his colleagues went on to hypothesize that sdLDL promotes atherosclerosis because of its ability to penetrate the artery wall more easily than large LDL. He and others subsequently showed that sdLDL are also more prone to oxidation than large LDL (1, 2).

Diet Affects LDL Subcategories

The next step in Krauss's research was to see how diet affects lipoprotein patterns. In 1994, he published a study comparing the effects of a low-fat (24%), high-carbohydrate (56%) diet to a "high-fat" (46%), "low-carbohydrate" (34%) diet on lipoprotein patterns. The high-fat diet also happened to be high in saturated fat-- 18% of calories. He found that (quote source):

Out of the 87 men with pattern A on the high-fat diet, 36 converted to pattern B on the low-fat diet... Taken together, these results indicate that in the majority of men, the reduction in LDL cholesterol seen on a low-fat, high-carbohydrate diet is mainly because of a shift from larger, more cholesterol-enriched LDL to smaller, cholesterol-depleted LDL [sdLDL].

In other words, in the majority of people, high-carbohydrate diets lower LDL cholesterol not by decreasing LDL particle count (which might be good), but by decreasing LDL size and increasing sdLDL (probably not good). This has been shown repeatedly, including with a 10% fat diet and in children. However, in people who already exhibit pattern B, reducing fat does reduce LDL particle number. Keep in mind that the majority of carbohydrate in modern America comes from refined wheat and sugar; a diet of unrefined carbohydrate may not have these effects. Krauss then specifically explored the effect of saturated fat on LDL size (free full text). He re-analyzed the data from the study above, and found that:

In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid [as well as palmitic acid], was associated with increases in larger LDL particles (and decreases in smaller LDL particles). LDL particle diameter and peak flotation rate [density] were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL.

Participants who ate the most saturated fat had the largest LDL, and vice versa. Kudos to Dr. Krauss for publishing these provocative data. It's not an isolated finding. He noted in 1994 that:

Cross-sectional population analyses have suggested an association between reduced LDL particle size and relatively reduced dietary animal-fat intake, and increased consumption of carbohydrates.

Diet Affects HDL Subcategories

Krauss also tested the effect of his dietary intervention on HDL. Several studies have found that the largest HDL particles, HDL2b, associate most strongly with HDL's protective effects (more HDL2b = fewer heart attacks). Compared to the diet high in total fat and saturated fat, the low-fat diet decreased HDL2b significantly. A separate study found that the effect persists at one year. Berglund et al. independently confirmed the finding using the low-fat American Heart Association diet in men and women of diverse racial backgrounds. Here's what they had to say about it:

The results indicate that dietary changes suggested to be prudent for a large segment of the population will primarily affect [i.e., reduce] the concentrations of the most prominent antiatherogenic [anti-heart attack] HDL subpopulation.

Saturated and omega-3 fats selectively increase large HDL. Dr. B. G. of Animal Pharm has written about this a number of times.

Wrapping it Up

Contrary to the simplistic idea that saturated fat increases LDL and thus cardiac risk, total fat and saturated fat have a complex influence on blood lipids, the net effect of which is unclear. These blood lipid changes persist for at least one year, so they may represent a long-term effect. It's important to remember that the primary sources of carbohydrate in the modern Western diet are refined wheat and sugar. Healthier sources of carbohydrate have different effects on blood lipids.* This is why you may read that small, dense LDL is not an "independent predictor" of heart attack risk. Since it travels along with a particular pattern of HDL and triglycerides, in most studies it does not give information on cardiac risk beyond what you can get by measuring other lipoproteins.

118 comments:

I read somewhere (possibly here?) that the carbohydrate in rice is converted to some extent to Palmitic acid by the liver. If this is the case, it could be one factor explaining the incidence of coronary events in Asian vs. Western populations. Carb source, as you have noted before, trumps carb percentage in the diet.

Again, if this is the case, then Asian populations may in effect be consuming a high saturated fat diet even if rice forms the foundation of their meals.

I'm certainly not sure how the conversion of carb from rice into lipids in the liver compares to conversion from other carb sources. I may be totally off base in this comment.

I suggest following HBA1c, Triglycerides, HDL and (25) OH D levels to make sure one is on the right track. I think these four will prove to be the best predictors of mortality. I think LDL and total C can be safely ignored.

I recommend NMR lipoproteins be done only to fend off Statin-enthusiast physicians when total C or LDL are "high"

Do you think HDL is "cleaning" the vessels or do you agree all these numbers are just knock-on effects of a certain kind of (high fat) proper diet? I am guessing from your Kitavan posts you might favor the latter.

Great post, Stephan. Sometimes I only get a chance to scan your posts, but this one kept reigning my eyes back in to capture the details. Learned a lot with this post and it is very interesting, to say the least, that the conclusions seem to directly contradict the dietary recommendations of the AHA (per usual when you dig into the details of the matter).

I love RM Krauss's work. I have been following him around on pubmed since Peter introduced him to me in his "Age,Rage,Ale,etc" series of blogposts last year. His latest forays move away from "saturated fat may not be bad for you" (alot of his 1990-2002 work) into "fructose probably is not good for you." He is one of the authors of the article mentioned in this blog last month on just that theme.

Starch, whether from rice, wheat, or whatever, is rapidly broken down into glucose and dumped into the circulation. Glucose is glucose, regardless of its source. Excess glucose not needed for energy or to replenish glycogen stores is converted by the liver to palmitic acid.

Jen, yeah, I guess if I'd thought it through I would have figured that out...it's not like grains of rice are delivered to the liver by the bloodstream, having passed through the intestine undigested!

So, then, the key to effectively using carbs as a fuel source would be to get a pure a source for glucose production as possible. Meaning that all starches break down to glucose, which can be converted to palmitic acid, but some carbs carry the baggage of unwanted stuff, such as gluten. So rice fits that bill, to the benefit of Asians, but so would tubers such as taro or skinless potato, or high starch/low fructose fruits such as plantains.

But we shouldn't make too much of this, of course. Eating high starch is not necessarily the best road to a coronary-event-free life, but according to the Kitavans, and others, it certainly does not preclude such a heart-healthy condition. And the action of excess carb being coverted to palmitic acid could play a role in that.

What I find really intersting is this:

The body, when faced with an overabundance of glucose, converts that glucose to saturated fat. We certainly evolved to be able to consume carb, and therefore evolved to handle it appropriately, so the fact that we use it to make saturated fat and not some other kind of fat should indicate that the body prefers it. Or at least has evolved to thrive on it.

As Jen mentioned, all carbohydrate in excess of what can be immediately burned or stored as glycogen is turned into palmitic acid by the liver, whether it's from rice or any other source.

The higher the glycemic index, the larger the proportion that's converted to palmitic acid. That's because there's a brief rush of glucose so more gets turned into fat rather than burned as glucose as it trickles into the bloodstream more slowly.

I also think it's telling that the body chooses to convert carbs to palmitic acid, when we have the enzymes necessary to monounsaturate it.

Hi Kurt,

That sounds reasonable, although I do think there's some value to LDL particle count. I'm skeptical of the "reverse cholesterol transport" hypothesis of HDL, it just seems implausible on the surface. But I haven't really looked into it so maybe there's good evidence. I think it could easily just be acting as a marker of diet.

Homertobias,

I did notice he's on the fructose paper. He's done some great research over the years!

Robert,

I'll be posting on animal models of atherosclerosis at some point in the next few weeks because I think it's interesting. In general, the only animals that you can give atherosclerosis by feeding saturated fat are species that react to sat fat by dramatically increasing LDL. I'm talking about 3-10 fold or more in some cases. Typically but not always aided by large amounts of dietary cholesterol.

Then there are the species that react more modestly to sat fat (like humans), where it doesn't produce atherosclerosis on its own. Often researchers use what they call an "atherogenic diet" that's a mix of large amounts of cholesterol, saturated fat (often hydrogenated) and sugar, on the background of an otherwise highly refined diet. Feed this to an animal that's mostly or totally vegetarian and you're almost guaranteed to get blood lipid disturbances and massive atherosclerosis.

When the confounders of TG levels and HDL are taken in consideration much of the relavance of smLdl levels disappear.

For instance, when you compare folks at the same TG levels but differing in small and large LDL levels there's no difference CHD. Folks with the large LDL levels have just as much disease as the folks with greater smaller Ldl levels.

This same pattern is found in numerous case controlled and prospective studies 20 studies). When you properly account for confounders, both small and high density ldl levels are equivalent. Some studies have even found that the larger LDL particles are associated with disease.

Also, its been shown that the larger particles are directly arthogenic. Some types of the familial hypercholesterolemiaproduce a only the large LDL particles and these folks suffer from severe CAD sometime before the age of 20.

Also Among Native American communities,large LDL is more common where the CHD prevalenceis high.

The evidence indicates that both type of ldl are associated with disease and the best overall indicator is the total amount of LDL particles, not LDL-C or LDL size.

RegardsRandy

Ref:Low-Density Lipoprotein Size and Cardiovascular Disease: A ReappraisalFRANK M. SACKS AND HANNIA CAMPOSHarvard School of Public Health, Department of Nutrition, Boston, Massachusetts 02115

In other words, it's clear that both large and small ldl are responsible forLDL is responsible for their premature atherosclerosis.genitic

I addressed this in the post. How many times do we have to have this conversation.

sdLDL is a marker of heart attack risk, just like LDL particle number. If you could only measure one blood lipid parameter in the average American, you would get about the same amount of information about heart attack risk from measuring LDL size as measuring LDL particle number.

The fact that you can "adjust" it out mathematically using trigs and HDL doesn't change that fact. The only thing it changes is the practical application of it: there's not point in measuring LDL size when you can measure HDL or trigs more easily. But that has nothing to do with the relevance of sdLDL to coronary disease, it's just a practical matter of extracting the most info out of the patient as easily as possible.

Might you be opposed to using sdLDL as a marker because it's improved by saturated fat, perhaps?? Just a thought.

Stephan said:sdLDL is a marker of heart attack risk, just like LDL particle number. If you could only measure one blood lipid parameter in the average American, you would get about the same amount of information about heart attack risk from measuring LDL size as measuring LDL particle number.

Reply:No that's not what the paper said. The paper build a case on evidence that large LDL was as associated with CAD as small LDL.

This applied not only in cases where of high TG but low TG.

Stephan Wrote:Might you be opposed to using sdLDL as a marker because it's improved by saturated fat, perhaps?? Just a thought

Reply:No, I'm opposed to using smLDL as a marker becasue lgLDL is just a bad.

Once again the evidence was presented in the paper.

Please demonstrate this is so by references (from this paper) instead of declaring it so.

Do you claim that a that lgLDL is not arthogenic? I am claiming that it is with evidence presented from the paper.

But is LDL sperhical? - some think not - discoid with different paramaters controlling diameter and height

"Combined data from LDL composition and size measurement are compatible with a discoid particle shape"

http://www.jlr.org/cgi/reprint/45/5/954.pdf

Also the trial you cite says " Small, dense LDL has a low content of esterified and unesterified cholesterol, and phospholipid; the triglyceride content is either similar to (24) or greater than (25) large LDL. This reduced cholesterol content may be an effect of CETP (19, 20)."

which is at odds with suggestions I have seen elsewhere that the LDL cholesterol content is fairly stable. From a quick skim of the refs I could not obviously see where that claim came from.

Is there a simple trial that looks at the content of the various classes of LDL.

Could different densities be due to different packing arrangements antioxidant content etc?

They also say small LDL has a longer residencey time but the trial they cite suggests oestrogen net increased uptake. So how do you determine residencey time as against receptor affinity?

They say "Both large and small LDL compared with intermediate size LDL have reduced affinity for the LDL receptor which clears LDL from plasma"

And how does that relate to the number that actually cross the membrane? Common sense suggests that small LDL would be easier to get through the vascular walls.

OK but large LDL have more Vitamin E and so are better protected from oxidation.

They also say "Thus, a link between LDL oxidizability and human atherosclerosis and CHD remains to be established." which runs counter the general run of reading I have done on the subject.

On a net basis might bigger LDLs have more difficutly in crossing the membrane? Hence higher LDL figures for sat fats.

They would will spend longer in the circulation, but are better protected. Overall dependent on LDL levels and overall antioxidant status etc bigger LDL could become oxidised and so contribute to arterial deposits.

And then at what point do arterial deposits translate into vascualar disease?

That paper you presented as evidence against sdLDL is a review paper. It contains no new data. It doesn't change the fact that sdLDL has been associated with heart attacks over and over again, and often more tightly than LDL particle number. I've already provided several references for that, and the paper itself contains several as well.

There is no amount of intellectual wiggling that will get you around the fact that sdLDL has been associated with heart attack risk in the majority of prospective trials. You can argue that one with Ronald Krauss.

The paper uses the same argument that you're repeating over and over, that sdLDL is not "independently" associated with heart attacks, therefore it's not involved in CHD. That is a logical error.

The paper also admits that sdLDL are oxidized more readily than large LDL, then provides unconvincing test tube evidence for the atherogenicity of native LDL.

The fact that some FH patients have large LDL is meaningless. If your LDL is 350 mg/dL, it probably doesn't matter if it's large or small. But that has little relevance to the average person.

I just go to pubmed, type in an interesting author, and follow the links. Or I go to google scholar and do the same. There is so much out there. Recent articles on google scholar are also helpful.

Randi

Seems to me that Frank M Sacks is one of the major players in the Harvard crowd. This group on the one hand is dominated by Paul Ridker( longtime champion of HSCRP), Walter Willett, (emerging from his long association with Dean Ornish) I really like Peter Libby's work the best if we are talking the search for new CVD markers. What we don't need is 10 markers measuring the same thing. Frank Sacks seems to be more interested in carrier lipoproteins especially apo-C lll. Apo B particles carry differing amouts of apo-C lll. The higher the apo-C lll content, the more triglycerides in the particle, the more atherogenic it is and the smaller it is.....Are we all just looking at the same thing with different colored glasses?

Stephan Wrote:There is no amount of intellectual wiggling that will get you around the fact that sdLDL has been associated with heart attack risk in the majority of prospective trials. You can argue that one with Ronald Krauss.

Reply:Not when you account for confounders via multivariate analysis. Thats the point.

Here's some more refs:Quote:

Nov. 11, 2004 (New Orleans) — The number, not the size, of low-density lipoprotein (LDL) cholesterol particles predicts heart disease risk, according to an analysis of blood samples from more than 3,200 participants in the Framingham Heart Offspring Study.

http://www.medscape.com/viewarticle/493610

//******************************Quote:the MESA (Multiethnic Study of Atherosclerosis) study, Mora et al.[42] studied the association of LDL-P and particle size by NMR with carotid intima-media thickness (IMT) in over 5,000 apparently healthy individuals. When controlling for traditional CAD risk factors and LDL subclass correlation, both large and small LDL-P, but not LDL size, were significantly associated with carotid IMT.The LDL-P appears to be a particularly strong predictor of CAD in women. In the prospective CHS (Cardiovascular Health Study),[37] NMR-determined LDL-P and small LDL particle size predicted incident CAD, primarily among elderly women. The LDL-P remained significant, even after adjustment for traditional risk factors, whereas LDL particle size did not.

The references you cited illustrate my point nicely. In the MESA study for example, they found increased IMT with smaller LDL sizes as compared to larger sizes.

Only after "adjusting" for HDL and triglycerides did the difference become nonsignificant. That is a mathematical technique that does nothing to change the straightforward observation that sdLDL is associated with CHD just like LDL particle number. The references you provided support that.

Just because two variables co-vary does not make them both irrelevant. Conversely, you could probably "adjust" out the contribution of triglycerides and HDL using LDL size. Does that make triglycerides and HDL irrelevant?

Maybe, but who knows. Any of those blood lipid markers are irrelevant (except for diagnostic purposes) until we have good mechanism to back them up. There's a strong mechanistic basis for suspecting that sdLDL contribute to plaque formation more than large LDL. sdLDL get into the subendothelial space and get oxidized. Plus they're inherently more susceptible to oxidation. I agree with you that a higher concentration of LDL particles means there are more there to be oxidized (and may imply a longer plasma residence time as well).

I think it's interesting that the largest protective effect they found in the MESA study was from large HDL-- the one that's increased by saturated fat.

Conclusion: These data confirm our initial observation of familial aggregation of LMD. Moreover, in apparently healthy siblings of patients with LMD, this heritable component results in a risk increase for future events that is greater than that of a strong positive family history by itself.---------

The influence of genes on human life span has been confirmed in studies of life span correlation between related individuals based on family and twin data. Results from major twin studies indicate that approximately 25% of the variation in life span is genetically determined.-------

I could easily find thousands of papers that say basically the same thing - genetics is a significant component of degenerative disease. However very few authors of diet or lifestyle books will ever admit genetics are very important. Dr Doug McGuff in his writings on fitness training is one of the few exceptions.

"Apolipoprotein-B But not LDL Cholesterol Linked to Artery Calcium Build Up" - http://diabetesupdate.blogspot.com/2009/07/apolipoprotein-b-but-not-ldl.html Also, I think Apo-B is highly related with non-HDL cholesterol. But non-HDL equals LDL+VLDL. So, if LDL alone is not a good cardiovascular risk marker, then LDL+VLDL is a better one?

You're over-extrapolating my statement. In the context of modern non-communicable disease, what genetics do is determine your level of susceptibility to noxious diet/lifestyle factors.

Wild animals, including human hunter-gatherers, don't get heart attacks. Did we evolve the ability to have heart attacks, or did we simply exit our ecological niche?

100 years ago in the UK and US, heart attacks were rare. Now they're one of the top killers. Did our genes change in 100 years, or was it our environment?

Yes, there are some people who will do fine on industrial food due to lucky genes, but the point is that everyone can do fine on the food that our bodies are truly suited to.

The twin study you cited does not challenge that concept. It just illustrates that the right "risk factors" have not been identified by the study authors. For example, nearly everyone in the US eats a diet high in linoleic acid, so that can not be identified as a risk factor in the US population. Neither one of those twins would have had coronary disease in a hunter-gatherer context.

I like to apply the word "cause" to factors that have changed along with disease incidence, not those that have remained the same. Diet/lifestyle factors have changed along with a dramatic increase in CHD, overweight, diabetes, and many other disorders.

Chasing after genes is a red herring and will only lead to drugs, not prevention. Believe me, I see this at genetics conferences. Every talk ends with "and this discovery will help us design a pharmacological treatment strategy".

Use of tests to determine LDL particle count and size (NMR LipoProfile) has greatly helped me to understand the effects of diet on my lipoprotein patterns. A low carbohydrate diet has dramatically reduced total LDL-P count, and nearly eliminated sdLDL.

However, recently I have become less interested in LDL measurement, as it indeed does not seem to correlate to MI risk very strongly.

It appears that HDL, however, is much more strongly correlated to MI events and plaque growth.

It seems to me that the medical world (sorry for the generalization) is too focused on LDL, while giving too little attention to HDL. Maybe this is due to the pharmaceutical profit opportunity in promoting LDL lowering, whereas there is little pharma-commercial opportunity in raising HDL.

I am at a loss why my doctor wants to talk 'statins' when my LDL-C is around 190 ml/dl, LDL-P at 1400 sdLDL-P at 79, and HDL at 74 mg/dl.

More than one year ago, I followed the NCEPII diet recommendations, and the meaurements were: LDL-C 155 mg/dl, HDL at 36 mg/dl, and LDL-P over 2200.

Thanks for your story and the link! What ingredible progress you have achieved!

The low fat NCEP III and AHA Step I and II diets KILL people by increasing sd-LDL and lowering cancer- and cardio-protective HDL particles. What an abomination.

That HDL article you cited said "Between the start of the study and follow-up, about 20% of patients received HMG-CoA reductase in­hibitor (statin) treatment. The high density lipoprotein effect was markedly I-N-C-R-E-A-S-E-D when these patients were EXCLUDED from the analyses."

I agree with Stephan regarding genetic susceptibilty influencing disease patterns rather than genetics being the root of the issue. Many of the native cultures were hit especially hard by the transition from a traditional diet to an industrialized one. Perhaps it was the sudden availability of industrialized foods that wreaked havoc on people whose genes were used to a very different diet historically.

This is a disingenuous statement. Most mammals are completely protected against heart attacks regardless of lifestyle. The only notable exceptions are higher primates.

Advanced medical technology wasn't available to study true traditional HGs so it can't be proven whether they had heart disease or not. A stethoscope even in the hands of an expert cardiologist has very limited diagnostic capabilities.

Did we evolve the ability to have heart attacks, or did we simply exit our ecological niche?

We have always had the ability to have heart attacks. It is a characteristic of higher primates.

Stephan:100 years ago in the UK and US, heart attacks were rare. Now they're one of the top killers. Did our genes change in 100 years, or was it our environment?

One hundred years ago it was impossible to directly diagnose most heart attacks in live patients. The only tools available were a stethoscope and observing signs and symptoms. Even if patients died port-mortem examinations were rarely performed to determine the cause of death. Detailed medical statistics weren't kept then.

I am willing to accept heart attacks were less common 100 years ago but they certainly weren't rare events.

The hypothesis of this study was that chronic exercise would induce beneficial effects on cardiovascular outcomes, even in animals subjected to periodic social disruption (ie, stress). The study showed that, while exercise produced a significant conditioning effect on the cardiovascular system, it did not inhibit the progression of coronary artery atherosclerosis, lead to arterial remodeling (ie, luminal enlargement), or result in changes to plasma lipids or lipoproteins. Furthermore, the absence of an exercise effect on atherosclerosis was not influenced by exposure to the social disruption manipulation, which itself did not significantly affect atherosclerosis extent. Finally, animals that exercised displayed diminished cortisol responsivity to an ACTH challenge, suggesting that exercise attenuated the classic stress response of the pituitary adrenocortical axis; the social manipulation was not associated with any alterations in stress response. Taken together, the data presented here indicate that chronic exercise improves cardiovascular function and reduces stress responsivity without concomitant changes in plasma lipids or atherosclerosis progression.

Summary: Exercise protects against CHD but doesn't prevent atherosclerosis. This is what we see in the Masai - substantial atherosclerosis but few deaths from heart disease. eg Mann et al. 1972.

This isn't surprising as regular exercise increases vascularisation which significantly increases blood flow to the myocardium.

To Bris: If excercise would be a key ingredient, women should have much higer CVD rates than men. Instead, they have much lower rates everywhere.

However, excercise made but barely into the 9 most influential risk factors of multi-national Interheart (WHO's project, published in Lancet at 2004). Ans surprisingly, sex did not make into that list at all.

The trick is that sex factor is explained by the only cholesterol-related risk factor expressed there, i.e. the ApoB/ApoA-1 ratio. It all adds up to the higher HDL's in females.

... which all very nicely fits with Stephan's views. Besides, the risk factors were applicapble worlwide, including western and developing countries, which also effectively counteract the racial genetics card.

I'm afraid we just don't know how common CHD was before ~1900, but based on the severely atherosclerotic arteries of ancient Egyptians, I think it wasn't that rare. And here is an eye opening observation from the London physician William Heberden, made in 1772 (!), saved from the dust by Dr Malcolm Kendrick:

"But there is a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belonging to it,and not extremely rare, which deserves to be mentioned at more length. The seat of it and the sense of strangling and anxiety with which it is attended,may make it not improperly be called angina pectoris. Those who are afflicted with it are seized while they are walking (more especially if it be uphill, and soon after eating) with a painful and most disagreeable sensation of the breast, which seems as if it would extinguish life if it were to increase or to continue. But the moment they stand still, all this uneasiness vanishes. In all other respects the patients are, at the beginning of this disorder, perfectly well, and in particular have no shortness of breath, from which it is totally different.The pain is sometimes situated in the upper part, sometimes in the middle, sometimes in the bottom of the os sterni (breast bone), and often more inclined to the left than the right side. It likewise very frequently extends from the breast to the middle of the left arm. The pulse is, at least sometimes, not disturbed by this pain, as I have had opportunities of observing by feeling the pulse during the paroxysm. Males are more liable to this disorder, especially such as have passed their fiftieth year. After it has continued a year of more, it will not cease so instantaneously upon standing still: and will come on not only when the person is walking, but when they are lying down, especially if they lie on the left side and oblige them to rise out of their beds. In some inveterate cases it has been brought on by the motion of a horse, or a carriage,and even by swallowing, coughing, going to stool or speaking, or any disturbance of the mind Such is the most usual appearance of this disease;but some varieties may be met with. Some have been seized while they were standing still, or sitting, also upon first waking out of sleep; and the pain sometimes reaches to the right arm,as well as to the left and even down to the hands, but this is uncommon; in a very few instances the arm has at the same time been numbed and swelled. In one or two persons the pain has lasted some hours or even days; but this has happened when the complaint has been of long standing, or thoroughly rooted in the constitution; once only the very first attack continued the whole night. I have seen nearly a hundred people under this disorder,of which number there have been three women and one boy twelve years old. All the rest were men near or past the fiftieth year of their age. The termination of angina pectoris is remarkable.For if no accident interferes, but the disease goes on to its height, the patients all suddenly fall down, and perish almost immediately.

LeenaIf exercise would be a key ingredient, women should have much higer CVD rates than men. Instead, they have much lower rates everywhere.

It has been established beyond doubt that there are hormonal factors protecting women from CHD. This benefit disappears after menopause.

Women typically spend considerably more time doing physical activities than men. However tend to exercise at lower intensities. Low intensity activities such as walking tend to be very effective for heart health.

Melchior:I'm afraid we just don't know how common CHD was before ~1900, but based on the severely atherosclerotic arteries of ancient Egyptians, I think it wasn't that rare.

From studies of death certificates we can be reasonably sure that about 5-10% of people died from CHD around 1900. So it was actually extremely common. All physicians were familiar with the symptoms of angina pectoris, arrhythmias and congestive heart failure.

What really happened after 1915 was that a awareness of "heart attacks" (coronary thromboses) became much more prevalent in the medical profession. There was also a change in terminology.

In 1946 a leading physician in the UK stated that ‘Looking through my notes of patients seen 20 or 30 years ago, I come across cases where I failed to recognize the coronary thrombosis, which now, on paper, is the obvious diagnosis’.Cassidy M. Coronary disease. Lancet 1946;ii:588.

Since everybody has to die of something the causes of death have simply changed over the past 100 years. Once infectious diseases are eliminated more people must by default die of degenerative diseases. If CHD is eliminated people will then die from cancers or accidents.

There was a huge increase in CHD rates in the 1940s. However this also coincided with a huge increase in the older population - the group most vulnerable to CHD. The ability to diagnose CHD also increased substantially with the availability of ECG.

The problem with studying HGs is that very few of them live long enough to die of CHD which typically occurs in people aged in their 70s and 80s. I certainly wouldn't take the opinions of a dentist (Price) or an anthropologist (Stefansson) as proof of the absence of CHD in HGs.

I found this very interesting paper. The mortality rate of captive chimpanzees from heart disease is virtually identical to that found in humans. However the etiology of heart disease in humans and chimpanzees is very different.

What is most obvious is that as other causes of death such as infection were eliminated the heart disease mortality rate of Yerkes chimpanzees climbed from 11-36%. This is a mirror of what has happened in western society over the past century.

I agree. Even today there are probably differences in diagnosing and this obscures the picture terribly. In Japan, dying from a stroke is still regarded as heroic. Are doctors inclined to write ‘stroke’ on a death certificate when they are not really sure? It would only be human.

I politely disagree with your view on the protective effects of female hormones. Hormone Replacement Therapy does not lower the risk for CHD in postmenopausal women. This was one of the biggest recent medical ‘oopses’. Furthermore, a study in 1969 looked at young women who were hysterectomized. In one group they removed both the uterus and ovaries, in another group only the womb was removed (the sex hormone producing ovaries were kept in place). During follow up there was no difference in CHD-prevalence at all. Brasilian Women have just as much CHD as Brasilian men. I’m afraid this is an ad hoc explanation that doesn’t hold water, but I’m entirely prepared to change my mind if you have prove to the contrary.

Many doctors have indeed mentioned a sudden and steep rise in myocardial infarctions in the first half of the 20st century. Paul Dudley White comes to the mind. AnAmerican and a British physician independently reported it. But how much of this was due to a growing awareness? The letter by Heberden finally convinced me that MI’s were quite common in the 18th century.

I absolutely do not doubt the observations like those by Lindeberg et al on Kitava. These folks just don’t get CHD, while they do get it as soon as they leave the island. It’s also very hard to dismiss the 5-fold difference in CHD mortality between southern France and Scotland, and one cannot blame it on differences in perception and diagnosis.

The burning question that binds us all remains: what causes these differences?

Bris,

Thank you for that chimp study. While you are playing with the interesting thought of a lack of early exposure to pathogens, I’m biased towards gluten containing grains and psychosocial stress. A Swedish group is identifying gluten as the trigger of an autoimmune reaction in arteries, while prolongued psychosocial stress can cause CAD and MI in all primates (via HPA-axis dysfunction).

The most important thing to remember is that people in western countries all have very similar life expectancy. The Scots die of CHD and the French from liver cirrhosis.

My personal view is that diet has a relatively minor role in CHD. Humans are omnivores with the ability to survive on a wide variety of foods. There are few rational scientific reasons why diet would have a major effect. The exceptions are in the cases of nutrient deficiencies or extreme diets.

People are far too concerned about their diets and make far too little effort to increase physical activity, get more sleep and minimise psychosocial stress.

The common factors for good health are plenty of sunlight, adequate vitamins and minerals, a relaxed lifestyle and moderate physical activity. Examples are Okinawa, Crete and Kitiva. Yet they all have radically different diets.

Could be, but why then were all the age old monkeys in Weindruch’s recently published CR-study completely CHD free?

Completely untrue. The experiments were performed on rhesus monkeys not chimpanzees. The control monkeys were systematically 20% overfed. A tporough analysis shows that no benefits were obtained by calorie restriction. The experiment is systematically discredited here:

BACKGROUND: A high incidence of heart disease, especially idiopathic cardiomyopathy (IC), is seen in chimpanzees (Pan troglodytes). METHODS: We reviewed clinical records and necropsy reports of 87 adult chimpanzees for possible causes of heart disease/IC. We examined age, sex, cause of death, weight, diet, environment, infectious diseases, experimental uses and clinical pathology. RESULTS: The overall prevalence of heart disease in chimpanzees was 67.81%; the prevalence of IC was 51.72%. The prevalence of IC was significantly higher in males (60.32%) than that in females (29.17%, P = 0.009). The prevalence of other heart disease was higher in females (25%) than that in males (12.70%, P = 0.165). Heart failure occurred in 47.13% of chimpanzees. Heart disease was the primary cause of death in 34.49% of chimpanzees; 29.88% died of unknown causes. CONCLUSIONS: We found no evidence that diet, environment, viral agents, experimental use or disease exposure contributed to the deaths resulting from IC in chimpanzees.

I sympathize with your view. We have to die from something, of course. All in all we have never lived so long and so good (I am speaking for countries comparable to Holland). It’s easy to get too hysterical about ‘health’.

But. I do think CHD is ‘brought upon us’ and that we can avoid it or delay its onset. I don’t see any evidence of genetic protection. Kitavans do move from Kitava. Staffan Lindeberg describes how he also examinates a middle aged ex-Kitavan male who lives in a mainland city (visiting relatives on the island while Lindeberg is there). This guy is the only one showing signs of metabolic syndrome and even CHD (I believe he had suffered a stroke). This is only one person, but people who leave the Tokelau islands have been studied and they do get diabetes and CHD. I agree, psychosocial stress and lack of UV-B are certainly involved (but sugar, wheat and too much n-6 are too, I suspect). At the moment Scottish males have the lowest life exptectancy in Europe, I believe they are doing even poorer than the Russians. Again, I agree that their harsh psychosocial environment (and booze) are heavily involved.

Robert Andrew BrownHow may patients would the Doctor have had over a life time?

Far fewer than you think. In Heberden's time most physicians treated only a handful of regular patients. Sometimes they would exclusively treat a single patient for months at a time. Physicians charged massive fees and only the very rich used them.

>Far fewer than you think. In Heberden's time most physicians treated only a handful of regular patients. Sometimes they would exclusively treat a single patient for months at a time. Physicians charged massive fees and only the very rich used them.<

Then this must bring into question how representative his observations were of the wider population.

The rich by then would have had access to sugar, refined flour, mega meals etc. which arguably is part of the problem today.

"The experiments were performed on rhesus monkeys not chimpanzees. The control monkeys were systematically 20% overfed. A tporough analysis shows that no benefits were obtained by calorie restriction. "

You need to read the study methodology carefully - the only way to "overfeed" an ad lib monkey would be forcibly with an NG tube. The controls were ad lib.

There were most definitely benefits to calorie restriction - reducing the diabetes rate from 40% to 0% is one benefit completely independent of death rates.

Bris said: "The problem with studying HGs is that very few of them live long enough to die of CHD which typically occurs in people aged in their 70s and 80s ..."

This is a myth that you might want to research further before making such statements. I recently posted commentary on a study that dispells the whole "nasty, brutish, short" perception of isolated HGs and instead finds them to commonly live into their 70s:

You said "Advanced medical technology wasn't available to study true traditional HGs so it can't be proven whether they had heart disease or not. A stethoscope even in the hands of an expert cardiologist has very limited diagnostic capabilities."

I think you're underestimating the amount of data available on the cardiovascular health of non-industrial cultures. Let me give you a few examples:

In the 1950s, Lee et al. conducted autopsies on 4,336 Ugandans, 576 Nigerians, 1,179 African-Americans and 946 Caucasian Americans. They found 1 case of MI in the Ugandan group, 2 in the Nigerian group, 171 in the African-American group and 242 in the Caucasian group (Am J Cardiol. 13:30, 1964).

Mann et al. assessed MI in the Masai by ECG and autopsy. Of 400 Masai examined by ECG, there was no probable evidence of infarction in any. The most prevalent age group was 45-54. In 60 autopsies between two studies, including a number of men over 40 years old, they found zero infarctions (J Atherosclerosis Res. 4:289. 1964; Am J Epi. 95: 26. 1972).

On Tokelau, 0.0% of men 40-69 had ECG suggestive of "definite or probable" infarctions. In the same age group, genetically identical Tokelauan migrants to NZ had a prevalence of 1.0%. Their level of exercise increased after migration to NZ due to manual labor jobs. The number of Americans with those ECG signs in the same age group from the Tecumseh study was 3.5% (Migration and Health in a Small Society, a summary of the Tokelau Island Migrant Study edited by Albert F Wesson).

Meyer et. al reported autopsy data for African Bantu and Europeans ages 25-70. Among 143 Europeans, he found 15 MIs. Among 196 Bantu he found none (Circulation. 29:415. 1964). There have been several autopsy studies in fairly traditionally-living Bantu, all of which have reported low levels of atherosclerosis and very low rates of MI.

Staffan Lindeberg's group found an undetectable rate of MI and stroke among several thousand Kitavans by ECG and extensive interviews. These people exercise only moderately, and have MI rates far lower than age-matches Swedes who exercise more than them:

Hirst et al. autopsied 203 Thais from Bangkok and 514 Americans from LA. They found a MI rate of 2.7% in Bangkok and 24% in LA. Thais also had much less atherosclerosis. Exercise is not a compelling explanation for the 10-fold difference here because we're comparing two urban environments (Am J Clin Path. 38:162. 1962).

Morris et al. and Finlayson et al. published the two most definitive studies available of MI in the UK over the last century +, based on extensive autopsy data. They both concluded that MI was rare 100 years ago:

Everywhere you look, it's the same story. MI is a disease of industrial civilization, and neither genetics nor exercise can fully account for it. Although I do acknowledge that exercise is an important factor.

I just wanted to point out that the idea that the rhesus monkeys in the lifespan study were overfed is a misinterpretation of the data. What the investigators did was give the monkey access to 20% extra food, which is the only way to ensure ad libitum intake. They did not force feed the monkeys.

Stephan:"Staffan Lindeberg's group found an undetectable rate of MI and stroke among several thousand Kitavans by ECG and extensive interviews."

An interview and a resting ECG of 10% of the population is hardly a definitive study.

My sister recently had a full heart exam by a cardiologist. Her stress ECG showed no problems and indicated that she was above average fitness. However an angiogram showed she had severe atherosclerosis.

My mother was feeling unwell and had a home visit by our family doctor who was a specialist cardiologist (Australian six year cardiac Fellowship) with 40 years experience. He didn't detect any heart problems. Six hours later she was dead. A post mortem discovered a massive infarct had occurred 2-3 days earlier.

So I am always very suspicious when anyone claims that a "study" shows that a particular group doesn't have CHD.

Uffe Ravnskov author of The Cholesterol Myths has stated that only a post-mortem by an experienced pathologist complete with an extensive patient history is adequate evidence for/against CHD. The only place this occurs is in Scandinavia where autopsies are routinely performed on all patients by specialist forensic pathologists.

FASEB J. 2003 Apr;17(6):690-2. Epub 2003 Feb 5.Genotype and age influence the effect of caloric intake on mortality in mice.http://www.fasebj.org/cgi/reprint/02-0533fjev1

The shift from AL (ad libitum)-->CR (calorie restricted)increased mortality in 17- and 24-month-old mice, whereas the shift from CR-->AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.

Staffan Lindeberg's group found an undetectable rate of MI and stroke among several thousand Kitavans by ECG and extensive interviews.

An interview and a resting ECG of 10% of the population cannot be regarded as a detailed study.

Systematic reviews have reported that the sensitivity of resting ECG abnormalities for CHD events is low. The prevalence of the most common ECG abnormalities (Q waves, left ventricular hypertrophy, bundle-branch blocks, and ST-segment depression) ranges from 1 percent to 10 percent

http://www.ahrq.gov/Clinic/3rduspstf/chd/chdrs.htm

So there is in fact a high probability that many Kitavans could have had CHD that wasn't detected.

My sister recently had a full heart exam by a cardiologist. Her exercise ECG showed no problems and indicated that she was above average fitness. However an angiogram showed she had severe atherosclerosis.

My mother was feeling unwell and had a home visit by our family doctor who was a specialist cardiologist (Australian six year cardiac Fellowship) with 40 years experience. He didn't detect any heart problems. Six hours later my mother was dead. A post mortem discovered a massive infarct had occurred 2-3 days earlier.

The above examples show why I am always very suspicious when anyone claims that a "study" shows that a particular group doesn't have CHD.

Uffe Ravnskov author of The Cholesterol Myths has stated that only a post-mortem by an experienced pathologist complete with an extensive patient history is adequate evidence for cause of death. The only place this occurs is in Scandinavia where autopsies are routinely performed on all patients by specialist forensic pathologists.

In Mann's study, the Masai did have atherosclerosis. However, they seemed to develop it very rapidly once they were no longer restricted to milk, meat and blood for cultural reasons (and had access to processed food). During the period where their diet was restricted to animal foods, atherosclerosis was low. I covered those studies here:

I agree with you that ECGs don't detect the majority of MIs. From what I've seen, autopsies seem to detect about 10X the MIs that you see with ECGs. What ECGs do is allow unbiased comparisons between populations. For example, if the rate of probable MI by ECG is 0.0% for Kitavans and 3.5% for Americans in the same age group, we can say that the rate of MI is probably much lower in the Kitavans.

ECGs alone don't allow you to say "Kitavans never have heart attacks", which is why Dr. Lindeberg took other measurements to bolster his case. The Kitavans didn't really get hypertension, overweight, hyperinsulinism or any of the other things that come along with MI risk. Plus, the Kitavans were totally unfamiliar with the characteristic symptoms of MI (although they were perfectly familiar with the symptoms of many other disorders they suffered from, typically infectious). Lindeberg's team also detected no impairments suggestive of stroke, even among the substantial elderly population. The only mental impairments they found were two people with congenital mental retardation.

Taken together, Lindeberg interpreted these findings to suggest that heart attacks and stroke are rare on Kitava, and I concur.

kurt:You are confused. Read the study. Ad lib vs 30% less than prior ad lib intake. Those were the parameters.

I have downloaded and read the original paper in its entirety via my university. It is two pages with little detail and many obvious flaws:

- the original cohort of 15 (male) monkeys is far too small for any valid statistical analysis.

- the addition of another 46 monkeys in 1994 still makes the statistical analysis practically worthless.

- 3x as many male as female monkeys were used.

- dietary needs were determined by ad lib baseline feeding. Monkeys invariably overeat in captivity so the controls were almost certainly monkeys that were already overeating by a considerable margin.

- The calorie restricted monkeys were almost certainly adequately fed rather than genuinely calorie restricted.

- the authors excluded any death that they didn't think was age related.

- no details of the diet are provided.

In reality the experiment was actually comparing a very small number of middle-aged overfed sedentary monkeys with another very small group of adequately fed sedentary monkeys.

The paper is remarkably vague on important details such as:

- what the monkeys were actually fed. - the ages of each monkey - the actual cause of death- no details of the weight, body composition or changes in individual animals is provided.

Two things make me very suspicious:

- Weinruch is a disciple of the late extremist uber-wacko Dr Roy Walford. Walford himself died 40 years earlier than he predicted from ALS. It is quite likely that Walfords calorie resritriction actually killed him as saturated fat is believed to reduce ALS symptoms.

- Weinruch stands to make a great deal of money by achieving a "successful" outcome.

"Completely untrue. The experiments were performed on rhesus monkeys not chimpanzees. The control monkeys were systematically 20% overfed. A tporough analysis shows that no benefits were obtained by calorie restriction."

I know Weindruch et al used Rhesus monkey's. Does that matter? You stated earlier that all primates are prone to CHD. I did not mention this study to discuss the effects of calorie restriction - which are probably massive also in humans - but to stress the fact that even the ad lib primates stayed CHD free. If one assumes, like you do, that primates are prone to CHD, then the total absence of CHD in these very old monkeys is peculiar.

I say it again, I find it striking that the Weindruch group (probably coincidentally) used a wheat free chow, which is pretty rare.

Your recent meta analysis on chimps is dealing with cardiomyopathy, not with CHD.

Keys' starvation study is very interesting. These poor blokes were fed a wheat based crap diet, deficient in protein. They showed all the signs of starvation. I don't think it has been studied, but I see in my environment how people on a pretty high fat 'paleo diet' spontaneously 'calorie restrict', yet don't get emaciated or neurotic at all. This is not a scientific observation. But it should trigger curiosity.

Stephan,

I agree with your interpretation of the Kitava study. In his book, Lindeberg elaborates on the accuracy of an anamnesis. People in this tight community know everything about each other. They accurately describe how aunt X or Y died 50 years ago and what symptoms she presented. The agony of unstable angina pectoris would not escape them, nor would yhe forget a man in his fifties 'suddenly falling down and perishing almost immediately.'

Melchior: don't think it has been studied, but I see in my environment how people on a pretty high fat 'paleo diet' spontaneously 'calorie restrict', yet don't get emaciated or neurotic at all. This is not a scientific observation. But it should trigger curiosity.

I am fairly certain that the people you know on paleo diets still have substantial body fat reserves. Most "paleo" diets are really just moderately low carb diets rather than true paleo diets.

Stefansson describes a case where he and his friends were so hungry that they dug up a cache of completely rotten caribou and gorged themselves on the raw meat.

I have been on an Inuit style 75-80% fat meat-based paleo diet for over 5 years with around 20g a day of carbs. I can assure you that even on 2500-3000Cal a day I get just as hungry as I would on any other diet.

I can't maintain my weight (183cm, 72kg) on 2500Cal a day. This is despite only moderate physical activity. So I doubt any HG would ever willingly choose a 1600Cal diet for more than one day.

I have also been on a military survival exercise with zero food for three days. I thought almost constantly about food and the hunger was extremely unpleasant.

That’s entirely possible. I have indeed no idea of their exact energy intakes, only an impression that they spontaneously eat less. One of these guys lost 15 kilo’s in two months without changing his exercise regime (non existent), which indicates decreased energy intake. He says he’s not hungry. He is not nearly as low carb as you are (have been). No wheat though. Please don’t bang your head against the wall, but my guess is that these anecdotic cases have lifted their gluten/WGA induced leptin resistance, effectively terminating their chronic hyperphagia ;-).

"My personal view is that diet has a relatively minor role in CHD. Humans are omnivores with the ability to survive on a wide variety of foods. There are few rational scientific reasons why diet would have a major effect. The exceptions are in the cases of nutrient deficiencies or extreme diets."

I am curious. Why do you eat an Inuit style high fat, low carb diet like I do if you think against all evidence that it is only genetics that determines CHD?

weren't there some studies that showed the human body tightly regulates monos and saturates in tissue so that eating one or the other really won't change tissue concentrations that much??--- I know that large amount of polyunsaturates will incorporate into tissue and throw off ratios a lot.

if the above is the case-- why not just try to eat a decent amount of monos- you won't get the saturated fat driven insulin reponse. (i'm always reading studies that show if i eat carbs with saturated fat, you get the larger insulin response, but not with monos)

people are always pointing out how carbs are converted to saturated fat, but I remember reading studies that said that if you are not overconsuming food-- the conversion is minimal at best-- looking at something like 12-14 grams of converted fat-- this is barely anything!

I see people on caloric restricted high carb diets (with 20%-30% fat) that have fantastic biomarkers with low trigs, high HDL, and blood sugar in the lower 80s-- (i've seen a lot of super low carb people with blood glucose in the 90s) <--- even if their trigs are in the 40s with HDLs off the chart. Peter at hyperlipid even said that you should eat more carbs up to 3 days before a blood glucose test to get adequate readings-- that kind of logic doesn't seem smart-- you should have the lower readings most of the time. If that comes from consuming carbs, I think you should consume carbs.

You don't have to caloric restrict to be healthy, but you do need to watch fructose and polyunsaturated fat intake.

I don't think saturated fat is innocent yet. You almost certainly get an increased insulin response when saturated fats are combined with protein or carbs in comparison when monos or polys are combined with carbs or protein.

It's entirely possible that a high sat diet is causing massive insulin resistance in the body that doesn't really matter when carbs are kept really low. Will this factor in at some point? maybe!

Here's the thing. Populations that eat a lot of saturated fat don't end up getting hyperinsulinemia. The Masai don't have it, the Tokelauans don't have it, the Kitavans don't have it and the French don't have it (as much as us anyway). In the US, saturated fat intake is decreasing as hyperinsulinism increases.

So even if saturated fat is able to increase post-meal insulin secretion (which it certainly doesn't do as well as carbohydrate in any case), it doesn't lead to insulin resistance. Neither saturated fat nor starch (per se) are behind the insulin resistance epidemic that we're seeing.

What we need to find are mechanisms that create chronic, fasting insulin resistance, not just elevated post-meal insulin. It probably has a lot to do with excessive omega-6. In mice, the insulin resistance/fatty liver/etc. brought on by a poor diet can be blocked by fish oil or COX-2 inhibitors. COX-2 is involved in generating omega-6 derived eicosanoids and omega-3 is an inhibitor of omega-6 eicosanoid production.

Sugar (fructose) can also cause insulin resistance.

I think the healthiest proportions of fatty acids are probably those that we evolved on-- natural animal fats. Low omega-6, balanced with omega-3, and roughly equal proportions of MUFA and SFA. MUFA are probably pretty harmless, but I don't see any reason to avoid natural saturated fats at this point. Particularly because they are often very nutritious, for example butter and red palm oil.

We know we need to consume a low fructose diet. Maintaining low total polyunsaturates with balanced omega 3/6 is beneficial. Consuming roughly 1:1 ratio of saturates to monos is good because our tissue concentration is close to that (a little bit more monos to sats in tissues).

What we don't know is what ratios of carbs and fats will lead to optimal longevity-- we can look to cultures that have longevity and what they have done-- but that doesn't always give us the answers we want.

I'm vary wary of consuming fats these days that have been altered in any way by temperature-- seems to be almost safer to just have your body produce the fats it wants (because they won't be damaged)

could you comment on this study stephan:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2648700

I know you can argue that the individuals in this study did not spend enough time getting "fat adapted" to deal with the extra H2O2-- but these are the type of studies that can make people rethink the really low carb diet-- epecially in terms of longevity-- and start to look at the Kitavan-type diet more.

Just took a look. I can't say I'm convinced. Mice increase their caloric intake, often dramatically, on a high-fat diet. They get fat, insulin resistant, etc. So was it the fat, the calories or the insulin resistance that caused an increase in mitochondrial H2O2? The chow looks like it also had a poor n-6:3 balance.

In the human part of the trial, they didn't describe the diet they used. I have to guess it was high in linoleic acid. If I recall correctly, LA is a "dirty" fuel for mitochondria, increasing the level of reactive oxygen species. Maybe Robert Brown can comment on this. In any case, without the diet composition, it's hard to interpret. They also didn't have a control group, which is poor form.

Even if high-fat feeding does increase H2O2, we can't necessarily go from there to saying it will shorten your life. I can't think of any direct evidence that high-fat diets shorten lifespan. The French eat one of the highest-fat diets of any industrial nation and have one of the highest life expectancies. But on the other hand, I don't think there's any direct evidence that low-fat diets shorten either (although I'd be surprised if going below 20% didn't have adverse consequences of some sort).

I sympathize with your idea of letting the body decide which fatty acids to make. Carbohydrate comes with its own set of risks though, blood sugar and glycation for example. At this point I think there isn't enough direct evidence to suggest avoiding either quality fat or quality carbohydrate if you're a healthy person. I'm willing to have my mind changed.

When people are fit and of normal weight-- i would assume that saturated fat consumption doesn't pose much of a risk especially with a 1:1 ratio of monos to sats-- but when i see studies that show a large insulin spike with carbs+saturated fat-- I'm left wondering, what the hell am i going to put my butter and cream on? I want to put my mind at ease. my concern is optimal longevity, not just being healthy.

I've been searching hyperlipid to find out where peter discusses how that without 3 days of higher carbohydrate intake-- blood glucose might test in the high range(90+) on a super high fat keto diet. if the diet is causing insulin resistance and saving any amount of glucose for the brain (maybe thats why there are 90+ blood glucose readings) isn't this the opposite of what people are trying to do on a high fat diet-- glucose in the blood would be available for crosslinkages--- higher carb higher monounsaturated sat diets (assume 27 to 40% fats) really seem to hit a sweet spot because i've seen blood glucoses in these studies are almost always in the lower 80s)

bottom line-- i have trust in foods like raw butter, raw cream and such (especially at the range of 27% to 45% fats)--- but what about people who are deriving 60-70% fats from these sources-- i might question that-- i also might question anyone that gets a lot of fat from cooked sources-- because your body has to uptake these fats before its burns them. (what if the fats are damaged)

I am curious. Why do you eat an Inuit style high fat, low carb diet like I do if you think against all evidence that it is only genetics that determines CHD?

I eat a high fat diet because I have Crohn's Disease and a high fat diet controls it completely.

I didn't say that only genetics determine CHD. I claimed that diet is probably a minor factor in CHD and that far too much emphasis is placed the role of diet in CHD. When I mentioned extreme diets I was actually referring to a lack of vitamins, minerals and EFA not high carbohydrate intakes.

The many paradoxes suggest that many diets can be healthy from the ultra high carbohydrate diets of Okinawa to the ultra high fat diets of Inuits. The common factors in overall health seem to be adequate micronutrients, moderate physical activity and low psychosocial stress.

My university faculty hosts the Exercise and Oxidative Stress Research Group (EOSRG). They study the role of exercise, antioxidants and micronutrients in heart disease and exercise performance. EOSORG generally consider cholesterol and saturated fats to be minor players in CHD.

Melchior:Please don’t bang your head against the wall, but my guess is that these anecdotic cases have lifted their gluten/WGA induced leptin resistance, effectively terminating their chronic hyperphagia ;-).

My view is that you generally keep on eating until you get the required nutrients and then stop. This occurs at a much lower calorie intake on a nutrient dense HG diet.

Low-carb diets can cause an increase in fasting glucose, but the total average glucose over the course of the day is still lower than with higher carb, as judged by HbA1c.

You said "bottom line-- i have trust in foods like raw butter, raw cream and such (especially at the range of 27% to 45% fats)--- but what about people who are deriving 60-70% fats from these sources-- i might question that"

I don't think that's unreasonable. The Masai and Samburu got nearly 2/3 of their calories from dairy fat and seemed to do well, but was it truly 100% optimal? I doubt it. But mostly because dairy isn't "paleo", rather than because of the fat percentage. Dairy is an exceptionally nutritious food but it does cause problems for some people. 2/3 calories from "paleo" animal fats is well within our ecological niche. But not necessarily ideal for every individual.

I'm not too concerned about cooked foods, personally. But I think it's good to eat some raw food.

Aaron:Are you sure that someone like Peter on his "hyperlipid" diet (80% saturated fat) has insulin resistance? Are there studies that show such a diet causes insulin resistance to which you can point me?

I'm not sure that you can tell there is insulin resistance simply by measuring fasting blood glucose unless insulin is also measured. If he also had high insulin then sure, I'd be convinced.

People on high carbohydrate diets often have reactive hypoglycemia and may have what is now considered "normal" glucose levels in the 80s, but is that really normal? Without measuring insulin, we have no idea how much insulin they are pumping out to keep these low levels of blood sugar. Perhaps someone like Peter is not pumping out much insulin at all, so instead of being insulin resistant, he has what really is normal blood glucose, and probably very stable at that.

The "normal" fasting glucose number used to be at least 100, didn't it? As the Western diet has shifted to be more and more carb-centric, it could be that more and more people have hyperinsulinemia, making it look like the lower fasting glucose numbers are "normal" when in fact they could be very unhealthy. As with other blood markers, who are we considering normal these days?

Anyway, I have concerns like you as we have also adopted a diet much higher in saturated fat and low in carbohydrates. The idea of such a diet actually causing insulin resistance is shocking to me so I'd like to learn more.

You said: "My view is that you generally keep on eating until you get the required nutrients and then stop. This occurs at a much lower calorie intake on a nutrient dense HG diet."

That's funny. Here I have first hand anecdotic experience. I'm a long distance cyclist (can't help it, addicted). About two times a year my wife and I push our rolling castles from Holland to her family in Sweden and back (we do between 100 and 175 km per day, carrying gear). In the early days we stuffed ourselves with all the cakes, cookies, chocolate paste, sweet breads and comparable crap we could carry. We were like rockets, but we crashed every 40 kilometers, at least. I think we stowed away around 8000 kcal per day. Later we started eating much more sensible (only 'real' foods) and experienced that we hold much, much longer (60 - 85 km between meals), on what I perceive as far fewer calories. Bruce Ames has the same explanation as you do. A fascinating idea. But why did't our bodies detect the vitamin pills we popped in our crap fueled days?

I would assume that the best diet for longevity would stem around a diet that maintained the lowest HbA1c. If you are right stephan in that low carb diets maintain lower HbA1c even with higher fasting glucose-- how would insulin sensitivity fit into the picture for the two diets-- insulin sensitivity might not mean much if you are mainly using fat for fuel.

I mainly wrote my comments to address people who are on 20grams or less of carbs a day-- i just don't think its a grood idea. I would assume your liver would be working overtime to process protein into glycogen (from food or your muscles).

I have always had this hunch that when you use stored glycogen in your muscles for fuel instead of fat-- you are bypassing some of the byproducts that are made during fat oxidation for fuel-- I wonder if there are any studies that have looked at this (do you know of any Stephan?)

I know that mitochondria get better at processing fat byproducts the higher your reliance on fat as a fuel source-- by why not just try to use carbs as a clean source-- if i am right that there are less byproducts.

I also wonder if some of the longevity of higher carbohydrate peoples are do to higher levels of SHBG <----- which are usually lowered on diets that are higher in fat-- i would assume that higher growth hormones would be detrimental to longevity-- as witnessed by the fact that shorter people live longer (they produce lower levels of growth hormones throughout there lives)

Blogs like Stephan's are set up to help people live better, to deconstruct and understand the best nutritional studies out there, and to remind people that the best guide we have to being healthy is to look toward the cultures of people who are "in fact" healthy.

Some low carbers out there seem to peach paleo nutrition like a religion. No doubt paleo nutrition is hands over fist better than the standard american diet. Eliminating refined foods, sugar, and polyunsaturated oils, you will be healthier. But to lump all carbohydrates into 1 bag ignores the practices of cultures that have thrived on carbohydrates.

My goals are a little bit different than most paleos- I want to maximize lifespan. The only way to get info on this to study what happens at the cellular level when different substrates of fuel are used in the body (like fat or carb). For myself, I never was fully able to acclimate to a super high fat diet-- even after 2 months. While I had decent energy and felt decent. I felt like my body was consistently stressed out. I have hypothesized that this was because of depressed serotonin production from a diet low in carbs. Once I introduced low fructose starches, my energy production was stable and strong and I never looked back.

I've settled on a diet that is:

low fructoselow polyunsaturated fatmedium in starchy carbs that are low in anti-nutrients

low in protein (4-8ozs a day) that is minimally cookeduse 2-3 tbsp a day of raw dairyfats

"I never was fully able to acclimate to a super high fat ... I have hypothesized that this was because of depressed serotonin production from a diet low in carbs. Once I introduced low fructose starches, my energy production was stable and strong and I never looked back."

I had a similar experience after adding in some starch to a diet that was fairly high in fat and low carb. I left a comment a while back stating that I assumed this was because the low carbs were overtaxing the adrenal glands. Some other posters suggested that was bogus and that "adrenal fatigue" was a myth. I have no idea whether that is true but have read from various sources that low carb can produce thyroid and/or adrenal issues. I think Atkins admitted this himself at least in regard to thyroid. Does anyone have any thoughts on whether low carb can be hard on the thyroid or adrenals? And Aaron, what is the mechanism by which low carb affects serotonin?

Senta wrote:Are you sure that someone like Peter on his "hyperlipid" diet (80%saturated fat) has insulin resistance? Are there studies that show such a diet causes insulin resistance to which you can point me?

Reply:There lots of published evidence to this effect. It seems that when lipolysis increases and serum FFA increase insulin sensitivity is much reduced. The question is if this has anyn long term negative effect.

Aaron:I mainly wrote my comments to address people who are on 20grams or less of carbs a day-- i just don't think its a grood idea. I would assume your liver would be working overtime to process protein into glycogen (from food or your muscles).

I'm one of those <20g carbs/day people. Why most people fail on ULC diets is that they don't wait long enough for full adaptation to occur (3-6 weeks). I now suffer mild reactive hypoglycemia if I consume >10g of carbs in a meal.

The liver isn't working overtime on an ultra low carb diet. It only needs to produce a trivial 3-4g an hour of glucose. Alternatively a combination of ketones, fatty acids, triglycerides, amino acids and lactate can all be used as cellular fuels.

Aaron. It realistically takes a minimum of 12-18 months to fully adapt to a <20g/day carbohydrate diet. This really needs to be done in small increments as many physiological and biochemical adaptations must occur. For a start there must be a huge increase in the number of mitochondria in muscle cels and a considerable increase in capillaries needed for extra blood flow to support aerobic metabolism.

Your experience with very low carb mirror mine. I just don't seem to adapt and I lose strength and stamina. As soon as I reintroduce some rice, potatoes and fruit, the 'machine' runs fine. Biased by this personal experience, I doubt if low carb is optimal. Like you I'm only interested in disease free longevity. Viljalmur Stefanson writes somewhere that although the Inuit lack the diseases of civilisation, not many of them live past ~70. There could be other reasons for that, of course. My (intuitive) strategy is to eat no more (gluten/WGA-free) carbs than my glycogen stores can carry (and to deplete them regularly).

Thanks for your thoughts Bris. I’m afraid you are right. My cognitive dissonance clouded my imagination, but I suddenly remember a semi arctic hike which almost killed me... in mid summer ;-). In the mean time I can ease my mind a bit with the Okinawans.

BTW, I see Stephan did a post on the life expectancy of the Inuit in july 2008.

Thanks randy and Bris. Peter claims he eats enough carbs to stay out of ketosis, do you still think he is insulin resistant? Even if he is, it doesn't sound like it's the same kind of dangerous insulin resistance seen in metabolic syndrome, when the insulin receptors shut down due to excess insulin. With lower carbohydrates, the receptors down-regulate because they are not needed. Is the type of insulin resistance caused by extremely low carb diets easily reversed if necessary? Do you know where the "sweet spot" is (how many grams of carbohydrates to avoid either kind of IR)?

I doubt my husband and I have to worry about this - we don't count calories or grams but we definitely are not up to 80% saturated fat or anywhere as low as under 20 grams of carbohydrate.

Hopefully Stephan will write a post about high saturated fat diets and insulin resistance some day!

I'd like to clarify-- I never said Peter at hyperlipid "is" insulin resistant-- only that i fear that his diet may lead to it over time!

I know he eats 20+ carbs a day (I worry when you are under this)-- in fact he eats in the range of 50 carbs a day-- way more sensible in my mind if you are doing low carb, high fat!

In terms of his sat to mono ratio--- if you look at the fact that he eats a lot of cream and butter-- once you throw out the short chain fatty acids (which are totally beneficial in my mind-- his sat to mono ratio would be close to 1:1)

My body runs well on starch-- and i don't seem to have all those microbial imbalances (Dysbiosis) that some low carb bloggers fear will happen from the fermentation of carbs. I eat carbs from sources that are low in mineral inhibiting substances. I see no problem with keeping your liver stacked with glycogen from fructose as long as you are not overdoing it!

Once again-- my hunch is that an overreliance on fats for fuel would in fact over time cause mitochondria to pump out more waste material (in comparison to carbs)-- while most people would like to see the large increases in mitochondria from a high fat diet (i'm not so sure)-- you have to understand that using "any" fuel source has its drawbacks.

As per a high fat diet messing up the adrenal glands-- I will let people in on my personal history. Even with copious amounts of fiber and whole foods-- most people in my family are prone to hemorrhoids.While i don't usually get huge ones-- on occasion, i can feel a bulge.

What is interesting here-- is that i usually get a slight bulge if i take carnitine- take stimulants, or go on a very high fat diet (i assume because all 3 promote fat burning!!). On all three things-- i feel energy and a wakefullness that makes it hard to sleep. I could eat fat all night and still not get that tired.

As soon as i introduce more carbs to my diet-- my body relaxes-- i sleep better, my bulges go away-- that is my story-- high fat diets may affect others differently.

Peter refers to this as physiologic insulin resistance and it makes perfect sense to me. I speculate that this type of IR is completely different from the type that is pathologic and caused by chronic hyperinsulinemia and fructose. For one thing, it seems to be quickly reversible on the time scale of hours if not minutes.

IR per se is not a disease - hyperinsulinemia and glycosylation are diseases and these phenomena are merely accompanied by IR in the metabolic syndrome.

You also said:

"Even with copious amounts of fiber and whole foods-- most people in my family are prone to hemorrhoids.While i don't usually get huge ones-- on occasion, i can feel a bulge."

You should very seriously consider that your hemorrhoids are actually caused by fiber and not be surprised that they are not amelioratied by it. (Personal and clinical experience)

The lower your fiber and starch consumption, the more normal will be your colonic motility. You may be constipated for a few weeks until your colon adjusts, then it will be smooth sailing.

Why do you care about feeding bacteria in your colon? They don't particularly care about you.

thanks for chiming in Kurt, I really value what you are trying to do with your blog.

Sorry Stephan for getting a little off topic-- the quality of the discussions on here merit a private forum!

IR per se is not a disease - hyperinsulinemia and glycosylation are diseases and these phenomena are merely accompanied by IR in the metabolic syndrome.

I agree with what you say-- but i want to see more studies done on healthy (non diseased people) to show if the byproducts of fat metabolism are more damaging over time vs carb metabolism (which may or may not be the case--)

http://www.eurekalert.org/pub_releases/2007-12/cp-fdo112707.php

the above study is interesting-- by increasing UPC1-- these mice are living longer-- a high fat diet by default would increase the number of mitochondria, and therefore, there would be overall increases in beta oxidation in the body-- especially on a low polyunsaturated fat diet -- because polyunsaturates increase uncoupling proteins (while saturated fats support beta oxidation). I wanna know if fat oxidation is more damaging than carb oxidation (remember, were talking about glucose here-- not fructose-- with the assumption that the body is going to store the carbs as glycogen in muscle-- and not convert the excess because of excess calories-- and we are considering a healthy metabolism)

As per my condition-- i really don't get many bulging veins-- they are almost always caused by too much drinking, too many stimulants, too much stress, or in my case--diets extremely high in fat and low in carb (which i think has to be some kind of dopamine/serotonin issue going on)

As per fiber, my stools have always been the best when i include some fruit, minimize vegetable intake, and include carbs in the form of stuff like buckwheat, barley, or root veggies.

While on a high fat diet consisting of cream, butter,olive oil, meat,fish,and small amounts of fruit and veggies and almost no nuts-- after about a week or so, my stools because less well formed- and progress to stay that way for weeks-- it resolved itself with the addition of foods like the above (buckwheat potato, etc.)

I don't think you need lots of fiber-- but i feel like it helps to have some. Fiber seems to do similar things for the body as adding probiotics to the mix.

I think the reason why you have to maintain a greater intake of probiotic type organisms on a higher fat diet is because fermentative bacteria seem to die out and get replaced by putrefactive bacteria-- and while i don't recommend a vegan diet to increase fermentative bacteria via fiber and low to no meat products-- fermentative bacteria do produce beneficial compounds for us: such as:

Phenol and p-cresol concentrations in serum and daily outputs in urine significantly decline in cases of a fiber adequate diet-- or with the supplementation of probiotics

the bacteria in my stomach may not care about me-- but I care about what they do for me

I'll chime in with a little about myself. I went low-carb for a while about 2 years ago after reading "Good Calories, Bad Calories". I took to it fine, I felt good and I liked that I could skip meals no problem.

Then "Nutrition and Physical Degeneration" began creeping back into my brain (it always comes back to Price), and I found the Kitava study, which caused my cognitive dissonance to boil over. I added back non-gluten carbs and I feel good. Not necessarily better or worse than I did on low-carb. I love fat and I think I could do well on practically nothing but fatty meat/organs with a couple of potatoes a day. But I can't afford it and besides, I don't think it's necessary.

I do like how much more convenient it is to eat carbs. I feel hunger more than I did on low-carb, but I can still skip meals just fine. I'm probably eating about 52% fat, 35% carbohydrate, and 13% protein, but I never count. Roughly 3,500 calories a day. 5'9", 153 lbs, 7% body fat. That's 300 g carbs per day. I have no regard for glycemic index, I'll slam potatoes like the antidote's in them. My appetite goes way down when I'm not strength training, bike commuting, etc.

About fiber. I hate to admit it, but my digestion is better with some amount of fiber. But the type is critical. Unsoaked beans and grains don't go over well. The best is ground, fermented and cooked whole grains like the brown rice dosas I make almost daily. Eating whole grains like cooked brown rice isn't great, but if the texture is fine from grinding it's much better. That type of fiber is great on my digestion, better than vegetables although they're fine too. That's my personal experience.

Starchy root vegetables are also great for my digestion-- potatoes, sweet potatoes, taro, etc. It's all about texture. Chunks of fiber disturb my digestion, but I can tolerate a lot of fiber if the texture is smooth.

Stepahan:I do like how much more convenient it is to eat carbs. I feel hunger more than I did on low-carb, but I can still skip meals just fine. I'm probably eating about 52% fat, 35% carbohydrate, and 13% protein, but I never count. Roughly 3,500 calories a day. 5'9", 153 lbs, 7% body fat. That's 300 g carbs per day. I have no regard for glycemic index, I'll slam potatoes like the antidote's in them. My appetite goes way down when I'm not strength training, bike commuting, etc.

It is quite easy to stay healthy and in shape when you are young. After age 35 it becomes much harder.

With respect unless your body fat level was determined by Dual-energy X-ray Absortiometry there is no way you are 7% body fat. Caliper measurements and Bioelectric Impedence Analysis scales wildly inaccurate

Body fat levels below 12% are uncommon even in elite professional male athletes (I know a national level middle distance runner who has 14% body fat with a BMI of only 20). Olympic marathoners are typically ~10% body fat. Anything below 10% is extremely rare.

I'm on a low carb diet. I don't count exactly but my only source of carbs is some veggies which I do not think amount to more than 10grams a day.

When I started low carbing I was about about 14-16 percent body fat, over time I went down to 10, 7, and my last reading was 4 percent. You can make what you want of that. I imagine there may be some inaccuracies with the scale but all other people using it have remained at the same body fat level. 6'3, 153LBS. Went down from 183LBS.

You said "It is quite easy to stay healthy and in shape when you are young. After age 35 it becomes much harder."

I have to disagree. Most people my age (29) are not healthy or in shape. I'm not showing any of the metabolic precursors to outright dysfunction that you see in the general population, such as central adiposity, insulin resistance, poor glucose control, high blood pressure, etc.

"there is no way you are 7% body fat."

Maybe so, but I'm not attached to the number in any case. I can see my abdominal muscles so I have very little fat, whatever the actual number is.

really? This is almost the exact opposite of what i have "thought" i've read-- do you have any studies to back this up?

I love it if there was some food source that was primary short chain fatty acids-- then we could duplicate the fatty acid profile other primates have.

My other question question still stands-- is there any studies out there to show if using carbohydrates for energy creates less byproducts in compared with fat metabolism. In terms of not generating as many free radicals.

If you had 4% body fat you would either be in a morgue or in a hospital on life support. Only a handful of world class athletes have ever been found to have as low as 6% body fat. That is only ever for a few days during competition. The only way to measure body fat accurately is with a DXA scan which costs about $200.

Stephan:

Abdominal muscles are often very well defined at 12-14% body fat. At 10% body fat you can see most subcutaneous veins and arteries clearly.

I didn't say that people under 35 are fit. I said it is much easier to stay fit when you are under 35. World record performance falls about 1% per year after age 35.

darnoconrad:I'm on a low carb diet. I don't count exactly but my only source of carbs is some veggies which I do not think amount to more than 10grams a day.

You won't get <10g/day carbs unless you are living on meat and black coffee. A cup of regular milk has 10g of carbs. Even a small amount of vegetables will get normally put you you over the 50g/day mark.

And, although one would not always suspect it, a much bigger brain. Now that this thread has drifted off so completely, what do you think of the idea that all these typical human changes are an adaptation to a coastal environment, as proposed by Hardy, Morgan and Cunnane? The Coastal Dweller Theory is often ridiculed, but in my humble opinion it's the best explanation available.

Now that this thread has drifted off so completely, what do you think of the idea that all these typical human changes are an adaptation to a coastal environment, as proposed by Hardy

Complete and utter rubbish. We evolved from tropical jungle dwelling frugo-insectovores who lived nowhere near coasts. Apes dislike water and will never immerse their heads. Untrained humans are probably the worst swimmers of any mammal species (except apes).

I am studying a postgraduate exercise science programme. Exercise scientists don't consider weight, body fat or cholesterol to be very important for health. Their argument is that fitness is much more important than fatness. In fact it is possible to be a exceptionally healthy and very fit with a BMI of 35. Most of the male exercise science faculty at my university are above average weight and not particularly lean.

My goal is not to maintain an identical level of fitness until I'm 80. It's to avoid chronic disease, feel good and remain functional. Slow decline in fitness is inevitable, but it's possible to remain very fit until 70 and beyond.

By the way, I'm skeptical that overweight is the healthiest weight. I acknowledge that in observational studies, risk of death is often lower in people who are overweight than in those who are obese and thin. I also acknowledge that a person can be overweight and athletic.

But overweight is not the natural state for our species. It's largely a product of industrial society. Even 40 years ago in the US, overweight and obesity were less prevalent. I suspect that the true optimum is to be rather thin. I'm not taking about rail-thin, because you do see hunter-gatherers with some body fat, but BMI over 25? I'm skeptical that it's the true optimum.

Aaron:You wrote:"I mainly wrote my comments to address people who are on 20grams or less of carbs a day-- i just don't think its a grood idea. I would assume your liver would be working overtime to process protein into glycogen (from food or your muscles).

I have always had this hunch that when you use stored glycogen in your muscles for fuel instead of fat-- you are bypassing some of the byproducts that are made during fat oxidation for fuel-- I wonder if there are any studies that have looked at this (do you know of any Stephan?)

I know that mitochondria get better at processing fat byproducts the higher your reliance on fat as a fuel source-- by why not just try to use carbs as a clean source-- if i am right that there are less byproducts."

Basic biochemistry will put your worries to rest.

If you're concerned about ROS and other radicals - the question is not settled. However, glucose oxidation has higher radical generation potential than beta-oxidation. The reason is two-fold: a) Unlike beta-oxidation glycolysis involves a lot of reactions featuring the generation of radicals as a part of the reaction mechanism. Rarely these highly reactive intermediates dissociate from the enzyme and can damage cellular components (glycolysis is located in the cytoplasm). b) Glucose oxidation produces a higher NADH/FADH2 ratio. What this means is that Complex I feeds more electrons into the electron transport chain compared to beta-oxidation. Complex I is the main site of premature electron leakage to oxygen and thus ROS generation.

As for the liver-gluconeogenesis thing - no, on a ketogenic diet body's need for glucose is reduced down to 30-50g per day (based on your body weight) and the liver is capable of producing many times more in 24h.

"There lots of published evidence to this effect. It seems that when lipolysis increases and serum FFA increase insulin sensitivity is much reduced. The question is if this has anyn long term negative effect."

The writer of this comment believes that diabetics (carbohydrate intolerant, by definition) should eat more carbs.

There may however be something to this: if I eat too many carbs and spike my BG, and eventually my insulin, I suffer from an increased insulin resistance which lasts for several hours.

How do I know? My BG shows raised on my meter but my muscles don't get any energy, so I assume the Glut-4 transporters shut down.

The time scale over which this occurs is not dissimilar to the time it takes to break the carbs down into trigs and get them into the blood and then manipulate the fats into store.

The exact opposite happens when I eat fats: the BG and insulin don't shift and my energy level stays up. Doing this long term until my body has adapted to fat/ketones rather than glucose as primary fuel has removed all my reactive hypoglycemia symptoms along with the hyperglycemia.

All of my lipid panels are in agreement that the lipids *in my blood* are raised by carbs, not dietary fat. This is undoubtedly one reason why most diabetics find insulin resistance drops dramatically from carbohydrate reduction. My trigs/HDL ratio fell (US numbers) from over 15 to around unity from carbohydrate reduction. Not at all uncommon.

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I'm an obesity researcher, neurobiologist, and author. In addition to my research, I enjoy synthesizing and communicating science for a general audience. I have a BS in biochemistry (University of Virginia) and a PhD in neurobiology (University of Washington).
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